Biodegradable polymers are widely used nowadays and have been designed for a broad range of medical applications and devices like implants in order to fulfill a temporarily mechanical function, such as for bone plates, sutures and the like and/or to deliver a drug locally in a controlled manner. In such applications, an implant material with an appropriate strength is required in order to provide a temporarily bridge in the bone defect.
In particular with respect to mechanical medical devices, a method is already known whereby cells having a desired function are grown on a prefabricated polymer scaffold, followed by transfer of the cell-polymer scaffold into a patient at a site appropriate for attachment in order to produce a functional organ equivalent. Success of this procedure mostly depends on the ability of the implanted cells to attach to the surrounding environment and to stimulate angiogenesis. The polymer scaffolding used for the initial cell culture is made of a material which degrades over time and is therefore no longer present in the chimeric organ. The preferred material for forming the matrix structure usually is a biodegradable synthetic polymer such as polyglycolic acid, polyorthoester, polyanhydride or the like, which is easily degraded by hydrolysis. This material may be overlaid with a second material such as gelatine or agarose in order to enhance cell attachment. In the case of making a cartilageneous structure, such a procedure is described namely in U.S. Pat. No. 5,041,138 making specific mention of polyglactin, a 90:10 copolymer of glycolide and lactide marketed by Ethicon Co. (Somerville, N.J.) under the trade name Vicryl®. The polymer matrix must provide an adequate site for attachment and adequate diffusion of nutrients and/or growth factors supplied during cell culture in order to maintain cell viability and growth until the matrix is implanted and vascularization has occurred. A preferred structure for organ construction therefore is a structure formed of polymer fibres having a high surface area which results in a relatively low concentration gradient of nutrients to achieve uniform cell growth and proliferation. Examples of such a technology are provided in EP-A-795,573 and U.S. Pat. No. 5,108,755. The latter discloses an implantable reinforcement device exhibiting relatively high stiffness, based on a substrate polymer selected from poly(orthoester), polylactic acid, polyglycolic acid and polycaprolactone, showing initial flexural strength and modulus (according to ASTM D 790-81) of 65 MPa and 1.6 GPa respectively. The said device retained 90% of its initial flexural strength and modulus at 6 weeks in vitro, but radiation sterilization reduced initial flexural strength by 60% and increased the degradation rate, thus severely compromising mechanical properties. Obviously a disadvantage of this kind of method is that the shape of the prefabricated polymer scaffold can hardly be changed at the time of implanting it into the patient.
In view of providing an implant, optionally with a drug system, into the body without incision, while avoiding the disadvantages of injected microparticles (which do not form a continuous film or implant with the structural integrity needed, and cannot be removed without extensive surgery if complication occurs), U.S. Pat. No. 5,278,202 discloses an injectable composition suitable for in situ implant within the living body, e.g. bone or the periodontal cavity, without the use of solvents, comprising:    (a) a pharmaceutically acceptable liquid acrylic ester-capped prepolymer formed from a low molecular weight oligomer having terminal functional groups able to react with acryloyl chloride,    (b) a pharmaceutically acceptable curing agent, and    (c) optionally a biologically active agent such as peptide and protein drugs.
U.S. Pat. No. 5,837,752 also discloses a composition in a form suitable for bone repair or replacement, bone cement or dental material. Following exposure to active species (such as photo-initiators or thermal initiators), it forms a solid semi-interpenetrating polymer network (i.e. a composition of two independent components being a crosslinked polymer and a non-crosslinked polymer), capable of supporting bone growth and repair, comprising:    (a) a linear hydrophobic biodegradable polymer,    (b) a monomer or macromer including a degradable anhydride linkage and containing a free radical (meth)acrylate polymerizable group, and    (c) optionally a reactive or non-reactive viscosity modifier,    (d) optionally therapeutic and/or diagnostic agents, and    (e) optionally porosity forming agents, including inorganic salts and proteinaceous materials with a particle size 100-250 μm.
The said composition can have a viscosity before crosslinking ranging from a viscous liquid suitable for injection to a moldable paste-like putty. Examples of hydrophobic polymers (a) include polyorthoesters, polydioxanones, polycarbonates, polyaminocarbonates, polyhydroxyacids and polyanhydrides. The only illustrated embodiment deals with network copolymerizing the methacrylic anhydrides of sebacic acid and 1,3-bis(p-carboxy phenoxy)propane. This composition has the disadvantage that therapeutic agents having a hydroxy or amine functionality reactive with the anhydride linkage must be incorporated indirectly, i.e. in the form of microparticles.
Among biodegradable polymers, special attention has been paid to polyesters and copolyesters, especially those based on lactones such as ε-caprolactone, glycolide and lactides. In particular, the controlled release of bioactive agents from lactide/glycolide polymers is described in U.S. Pat. No. 3,773,919. Also, U.S. Pat. No. 4,902,515 discloses encapsulating a biologically active ingredient in interlocked segments of poly(R-lactide) and poly(S-lactide).
Suitable polymer implants, in particular polyester implants, can be conventionally prepared while using biodegradable polymeric compositions obtained by solvent casting, filament drawing, meshing, extrusion-molding or compression-molding. Therapeutically active implants can similarly be prepared by dispersing a drug into a polymer matrix and then extruding the resulting mixture. Due to the usually high temperatures necessary for extruding polymers, such a procedure is obviously mainly limited to biologically active drugs with a substantially high thermal stability. This procedure is therefore not easily applicable to thermally degradable drugs such as most peptides and proteins. In many cases, the active forms of proteins are difficult to formulate together with biodegradable polymers.
For tailoring a biological material to the specific physico-chemical requirements encountered when a synthetic load-bearing (e.g. a hip) or non load-bearing (e.g. a cronal fracture) therapeutically active biodegradable bone implant is to be hardened in situ at the place where bone growth is expected, numerous factors have to be taken into account. First, when a degrading polymer matrix comprises a sequence, such as a polyester or a polyorthoester, which is able to generate acidic compounds such as lactic acid or glycolic acid, the growing medium for bone forming cells such as osteoblasts becomes too acidic and constitutes an unfavourable environment for bone reconstruction. Therefore there is a need in the art for an in situ implantable biological material suitable for bone reconstruction and which overcomes the problem of acidic polymer matrices, in particular a composition able to provide a slightly alkaline medium in the implant, thus favouring interaction with osteoblasts. Secondly, there is also a need in the art for injectable compositions suitable for in situ implant within the living body, based on liquid capped prepolymers, which are able to degrade more quickly. Thirdly there is also a need for biodegradable in situ implantable compositions, the leaching time of which can be better spread or controlled, for instance wherein the active-ingredient does not leach out of the matrix before the said polymer matrix degrades. Consequently, as a general rule, there is a need for the design of specific biocompatible crosslinkable polymer formulations, which are able to meet specific requirements for use as implant materials for the healing of bone defects or in the fixation of dental implants.